Thus, a key study by Welch and coworkers allowed to propose that HSCs/HPCs accumulate benign background mutations as function of age; the initiating mutations occur at a given time in this mutational background and are different for various AML subtype (i.e., PML-RARα fusion gene for APL, NPM1 or DNMT3A or IDH1 or TET2 mutations for M1 AMLs): Since this initial mutational event provides a clonal advantage, all the pre-existing mutations are captured in this initial founding clone [11]. The gene discussed is NPM1; the disease is acute promyelocytic leukemia.